Pharmaceutical compositions

ABSTRACT

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and/or a SGLT-2 inhibitor drug, and metformin XR, processes for the preparation thereof, and their use to treat certain diseases.

The present invention relates to pharmaceutical compositions containinga fixed dose combination (FDC) comprising a DPP-4 inhibitor drug(particularly1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,also named linagliptin) and/or a SGLT-2 inhibitor drug (particularly1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,also named Compound “A” herein), and metformin (particularly metforminhydrochloride) in extended release form (metformin XR); processes forthe preparation thereof, and their use to treat certain diseases.

In particular, the present invention relates to a pharmaceuticalcomposition comprising a fixed dose combination of an extended releaseform of metformin hydrochloride, optionally seal coated, which isfurther coated with an immediate release form of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(linagliptin) and/or1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene(Compound “A”).

Further, the present invention relates to a pharmaceutical composition,particularly a solid preparation (e.g. an oral solid dosage form, suchas e.g. a tablet), comprising or consisting essentially of

-   -   a) an inner extended release core comprising metformin        (particularly metformin hydrochloride) and one or more        excipients;    -   b) an optional intermediate seal coating; and    -   c) an outer immediate release coating comprising at least one        active pharmaceutical ingredient selected from        -   a DPP-4 inhibitor, preferably linagliptin, and        -   a SGLT-2 inhibitor, preferably Compound “A”,        -   and one or more excipients.

In a more detailed aspect, the present invention relates to apharmaceutical composition, particularly a solid preparation (e.g. anoral solid dosage form, such as a tablet) of a selected dipeptidylpeptidase-4 (DPP-4) inhibitor (preferably linagliptin, particularly inimmediate release form) and metformin (particularly metforminhydrochloride) in extended release form (metformin XR). In oneembodiment of this aspect, the present invention relates to apharmaceutical composition, particularly a solid preparation (e.g. anoral solid dosage form, such as a tablet), comprising a fixed dosecombination of an extended release form of metformin hydrochloride,optionally seal coated, and further coated with an immediate releaseform of linagliptin.

In another more detailed aspect, the present invention relates to apharmaceutical composition, particularly a solid preparation (e.g. anoral solid dosage form, such as a tablet) of a selected SGLT-2 inhibitor(preferably1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,particularly in immediate release form) and metformin (particularlymetformin hydrochloride) in extended release form (metformin XR). In oneembodiment of this aspect, the present invention relates to apharmaceutical composition, particularly a solid preparation (e.g. anoral solid dosage form, such as a tablet), comprising a fixed dosecombination of an extended release form of metformin hydrochloride,optionally seal coated, and further coated with an immediate releaseform of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.

In a further more detailed aspect, the present invention relates to apharmaceutical composition, particularly a solid preparation (e.g. anoral solid dosage form, such as e.g. a tablet), comprising

a first component, part or composition comprising metformin(particularly metformin hydrochloride) in extended release form and oneor more excipients, and

a second component, part or composition comprising a selected dipeptidylpeptidase-4 (DPP-4) inhibitor (preferably linagliptin), particularly inimmediate release form, and one or more excipients.

In particular, the present invention relates to a pharmaceuticalcomposition, particularly a solid preparation (e.g. an oral solid dosageform, such as a tablet), comprising an extended release form ofmetformin hydrochloride, optionally seal coated, and further coated withan immediate release form of linagliptin.

In another further more detailed aspect, the present invention relatesto a pharmaceutical composition, particularly a solid preparation (e.g.an oral solid dosage form, such as e.g. a tablet), comprising

a first component, part or composition comprising metformin(particularly metformin hydrochloride) in extended release form and oneor more excipients, and

a second component, part or composition comprising a selected SGLT-2inhibitor (preferably1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene),particularly in immediate release form, and one or more excipients.

In particular, the present invention relates to a pharmaceuticalcomposition, particularly a solid preparation (e.g. an oral solid dosageform, such as a tablet), comprising an extended release form ofmetformin hydrochloride, optionally seal coated, and further coated withan immediate release form of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.

In a yet further more detailed aspect, the present invention relates toa pharmaceutical composition, particularly a solid preparation (e.g. anoral solid dosage form, such as e.g. a tablet), comprising

-   -   a) an inner extended release core comprising metformin        (particularly metformin hydrochloride) and one or more        excipients,    -   b) an optional seal coating, and    -   c) an outer immediate release coating comprising a selected        dipeptidyl peptidase-4 (DPP-4) inhibitor (preferably        linagliptin) and one or more excipients.

In another yet further more detailed aspect, the present inventionrelates to a pharmaceutical composition, particularly a solidpreparation (e.g. an oral solid dosage form, such as e.g. a tablet),comprising

-   -   a) an inner extended release core comprising metformin        (particularly metformin hydrochloride) and one or more        excipients,    -   b) an optional seal coating, and    -   c) an outer immediate release coating comprising a selected        SGLT-2 inhibitor (preferably        1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene)        and one or more excipients.

Particularly, the pharmaceutical compositions of this invention comprisean inner core formulation of metformin hydrochloride comprising aswellable and/or extended release material.

In an embodiment, the pharmaceutical compositions of this inventioncomprise an inner extended release core which is a formulation (e.g.matrix formulation) comprising metformin hydrochloride, a swellableand/or extended release material, and one or more further excipients.

Particularly, the pharmaceutical compositions of this invention comprisean outer coat of active pharmaceutical ingredient (API) (linagliptinand/or1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene)in an immediate release polymer film.

Further, the present invention relates to a coating process (e.g.coating technology and processing conditions) and immediate releasecoating formulations of active pharmaceutical ingredients (API) in lowdoses (typically in doses of 0.5 to 25 mg) on top of tablet corescomprising active pharmaceutical ingredients (API) in high doses(typically in doses of 500-1500 mg) preferably, but not exclusively onextended release tablets. Anyhow, essential parts of the formulation andthe process of this invention may be also applicable to any other fixeddose combination with the described setting.

An aim of the present invention is to provide a pharmaceuticalcomposition comprising a combination of a selected DPP-4 inhibitor(preferably linagliptin, particularly in immediate release form), andmetformin (particularly metformin hydrochloride) in extended releaseform. Another aim of the present invention is to provide apharmaceutical composition comprising a combination of a selected SGLT-2inhibitor (preferably1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,particularly in immediate release form), and metformin (particularlymetformin hydrochloride) in extended release form.

The objectives of are to identify suitable formulations and processingconditions, such as e.g. of a coat of linagliptin or of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneon top metformin XR cores, providing adequate:

-   -   Chemical stability of the API (particularly linagliptin) in the        API film coat,    -   Assay of linagliptin or        1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene        in the API film-coat (e.g. 95-105%),    -   Content uniformity of linagliptin or        1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene        (e.g. RSD<3%) in the API film-coat,    -   Low defect rate of the API-film during film coating process,    -   Fast dissolution of the API from the API film-coat and no        changes of XR Metformin HCl dissolution, due to the API coating        with immediate release of linagliptin or        1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,    -   Processing aspects of coating process/technology, processing        conditions and immediate release API (linagliptin or Compound        “A”) coating formulations (API film coat),    -   Processing aspects of coating process/technology, processing        conditions and immediate release API (linagliptin or Compound        “A”) coating formulations on top of metformin extended release        tablets.

A particular objective of the present invention is to provide apharmaceutical composition and suitable coating process with very broadrange of drug substance (linagliptin or Compound “A”)/drug substance(metformin) ratio: 1:400-1:40. And the ratio of very low dosed API, e.g.linagliptin with 1 mg or 2.5 mg to very high dosed metformin with 1000mg and more. And the suitable immediate release dissolution of the lowdosed API with high dosed extended release metformin.

The unit dosage strength of the metformin hydrochloride forincorporation into the fixed-dose combination of the present inventionis 500, 750, 850 or 1000 milligrams, or even more (e.g. 1500 mg).

These unit dosage strengths of metformin hydrochloride represent thedosage strengths approved in the U.S. for marketing to treat Type 2diabetes.

The unit dosage strength of linagliptin for incorporation into thefixed-dose combination of the present invention is 2.5 or 5 milligrams,or even less (e.g. 0.5 mg or 1 mg).

The unit dosage strength of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenefor incorporation into the fixed-dose combination of the presentinvention is 5, 10, 12.5 or 25 milligrams.

Specific embodiments of dosage strengths for linagliptin and metforminhydrochloride in the fixed-dose combinations of the present inventionare the following:

(1) 5 milligrams of linagliptin and 1000 milligrams metforminhydrochloride;

(2) 2.5 milligrams of linagliptin and 1000 milligrams metforminhydrochloride;

(3) 2.5 milligrams of linagliptin and 750 milligrams metforminhydrochloride.

Specific embodiments of dosage strengths for1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand metformin hydrochloride in the fixed-dose combinations of thepresent invention are the following:

(1) 25 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 1000 milligrams metformin hydrochloride;

(2) 12.5 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 1000 milligrams metformin hydrochloride;

(3) 12.5 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 750 milligrams metformin hydrochloride;

(4) 10 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 1000 milligrams metformin hydrochloride;

(5) 10 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 750 milligrams metformin hydrochloride;

(6) 5 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 1000 milligrams metformin hydrochloride;

(7) 5 milligrams of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand 750 milligrams metformin hydrochloride.

(a) Metformin Part:

The first part in the present invention is a part (composition,particularly solid composition, e.g. a solid pharmaceutical compositionfor oral administration, e.g. tablet) comprising metformin (particularlymetformin hydrochloride) in extended release form, particularly anextended release formulation of metformin.

Exemplary extended release formulations of metformin are disclosed inU.S. Pat. No. 6,340,475; U.S. Pat. No. 6,488,962; U.S. Pat. No.6,635,280; U.S. Pat. No. 6,723,340; U.S. Pat. No. 7,780,987; U.S. Pat.No. 6,866,866; U.S. Pat. No. 6,495,162; U.S. Pat. No. 6,790,459; U.S.Pat. No. 6,866,866; U.S. Pat. No. 6,475,521; and U.S. Pat. No.6,660,300; the disclosures of which are incorporated herein in theirentireties.

A particular extended release formulation of metformin is described inU.S. Pat. No. 6,723,340, the disclosure of which is incorporated hereinin its entirety.

In an embodiment, the fixed-dose combination products of the presentinvention comprise—as first part—an inner core matrix formulation withmetformin hydrochloride dispersed therein, said matrix formulationcontaining an extended release material. The matrix formulation iscompressed into a tablet form.

In particular, the fixed-dose combination products of the presentinvention comprise—as first part—an inner core extended releaseformulation comprising metformin hydrochloride, hydroxypropylmethylcellulose (hypromellose), polyethylene oxide, microcrystallinecellulose, and magnesium stearate.

A particular extended release formulation of metformin is described inU.S. Pat. No. 6,723,340 as follows:

In an embodiment, the extended release material of the matrix comprisespoly(ethylene oxide) and/or hydroxypropyl methylcellulose (HPMC),preferably a combination of poly(ethylene oxide) and hydroxypropylmethylcellulose (HPMC), preferably at a weight ratio that causes thematrix to swell upon contact with gastric fluid to a size large enoughto provide gastric retention.

The poly(ethylene oxide) component of the matrix may limit initialrelease of the drug and may impart gastric retention through swelling.The hydroxypropyl methylcellulose (HPMC) component may lower the amountof poly(ethylene oxide) required while still allowing the swelling tooccur.

Preferably, the poly(ethylene oxide) has a viscosity average molecularweight of from about 2,000,000 to about 10,000,000 daltons, morepreferably from about 4,000,000 to about 7,000,000 daltons.

Preferably, the hydroxypropyl methylcellulose (HPMC) has a viscosity offrom about 4,000 centipoise to about 200,000 centipoise, more preferablyfrom about 50,000 to about 200,000 centipoise, even more preferably80,000 centipoise to about 120,000 centipoise, measured as a 2% solutionin water.

More preferably, the poly(ethylene oxide) has a viscosity averagemolecular weight of from about 4,000,000 to about 7,000,000 daltons, andthe hydroxypropyl methylcellulose (HPMC) has a viscosity of from about80,000 centipoise to about 120,000 centipoise, measured as a 2% solutionin water.

In an embodiment, the weight ratio of the poly(ethylene oxide) tohydroxypropyl methylcellulose (HPMC) is within the range from about 1:3to 3:1, preferably 1:2 to 2:1.

In a further embodiment, the weight ratio of the poly(ethylene oxide)and hydroxypropyl methylcellulose (HPMC) in combination constitutes fromabout 15% to about 90%, or from about 30% to about 65%, or from about40% to about 50%, by weight of the metformin part.

Tablet cores in accordance with this invention can be prepared by commontabletting methods that involve mixing, comminution, and fabricationsteps commonly practiced by and well known to those skilled in the artof manufacturing drug formulations. Examples of such techniques are:

(1) Direct compression using appropriate punches and dies, typicallyfitted to a suitable rotary tabletting press;

(2) Injection or compression molding;

(3) Granulation by fluid bed, by low or high shear granulation, or byroller compaction, followed by compression; and

(4) Extrusion of a paste into a mold or to an extrudate to be cut intolengths.

When tablets are made by direct compression, the addition of lubricantsmay be helpful and is sometimes important to promote powder flow and toprevent breaking of the tablet when the pressure is relieved. Examplesof typical lubricants are magnesium stearate (in a concentration of from0.25% to 3% by weight, preferably about 1% or less by weight, in thepowder mix), stearic acid (0.5% to 3% by weight), and hydrogenatedvegetable oil (preferably hydrogenated and refined triglycerides ofstearic and palmitic acids at about 1% to 5% by weight, most preferablyabout 2% by weight).

Additional excipients may be added, such as e.g. granulating aids (e.g.low molecular weight HPMC at 2-5% by weight), binders (e.g.microcrystalline cellulose), and additives to enhance powderflowability, tablet hardness, and tablet friability and to reduceadherence to the die wall.

An exemplary extended release metformin tablet core comprises metforminhydrochloride, a combination of poly(ethylene oxide) and hydroxypropylmethylcellulose (e.g. Methocel K100M) as a matrix for a swellableextended release tablet, microcrystalline cellulose as binder, lowmolecular weight hydroxypropyl methylcellulose (e.g. Methocel E5) asgranulating aid, and magnesium stearate as lubricant.

The composition of a representative metformin core tablet is provided asfollows:

metformin hydrochloride, e.g. 49.97% by weight of the first part,

poly(ethylene oxide), e.g. 26.50% by weight of the first part,

hydroxypropyl methylcellulose (e.g. Methocel K100M), e.g. 16.08% byweight of the first part,

microcrystalline cellulose, e.g. 4.99% by weight of the first part,

low molecular weight hydroxypropyl methylcellulose (e.g. Methocel E5),e.g. 1.70% by weight of the first part, and

magnesium stearate, e.g. 0.75% by weight of the first part.

Tablets may be formulated by dry blending a granulation comprisingmetformin hydrochloride and low molecular weight HPMC (e.g. Methocel E5)and the remaining excipients listed above, followed by pressing on atablet press.

Such an extended release matrix formulation of metformin is disclosed inU.S. Pat. No. 6,723,340 (e.g. Example 3), the disclosure of which isincorporated herein in its entirety.

As further example of a lubricant sodium stearyl fumarate may bementioned (e.g. at about 0.25-3% by weight).

In a further embodiment, the metformin extended release formulationallows for targeted, controlled delivery of metformin to the uppergastrointestinal (GI) tract. In a further embodiment, the metforminextended release formulation is a hydrogel matrix system and contains aswelling hydrophilic polymer and further excipients, which may allow themetformin tablet core to be retained in the stomach (‘gastricretention’) for approximately eight to nine hours. During this time, thetablet core's metformin is steadily delivered to the upper GI tract atthe desired rate and time, without potentially irritating ‘burst’ ofdrug. This gradual, extended release typically allows for more of themetformin drug to be absorbed in the upper GI tract and minimizes theamount of drug that passes through to the lower GI tract.

(b1) Linagliptin Part

In one variant, the second part in the present invention is a part(composition, particularly film coat) comprising linagliptin inimmediate release form.

In a particular embodiment, the fixed-dose combination products of thepresent invention comprise—as second part—a film coat formulation oflinagliptin, said film coat formulation comprising linagliptin, astabilizer for stabilizing linagliptin (e.g. a basic and/or nucleophilicexcipient, preferably L-arginine as stabilizer), a film-coating agent(such as e.g. hydroxypropyl methylcellulose, e.g. Hypromellose 2910,Methocel E5, or Methocel E15), a plasticizer (such as e.g. polyethyleneglycol, e.g. Macrogol 400, 6000 or 8000, or propylene glycol), and,optionally, a glidant (such as e.g. talc).

In an embodiment, the weight ratio of the L-arginine to linagliptin iswithin the range from about 2:1 to about 1:1, up to about 0.2:1.

The composition of a representative linagliptin containing film coat isprovided as follows:

-   -   linagliptin, e.g. 2.5 mg or 5 mg;    -   L-arginine, e.g. depending from need of stabilizer amount, e.g.        in the range from about 0.5 mg to about 10 mg (e.g. 5 mg);    -   hydroxypropyl methylcellulose (e.g. Methocel E5, Methocel E15,        or Pharmacoat 603 or 606), e.g. from about 25 mg to about 40 mg        (especially from 34.5 mg to 38 mg, or 34.5 mg);    -   polyethylene glycol (e.g. Macrogol 400, 6000 or 8000), e.g. from        about 0 to about 12 mg;    -   propylene glycol, e.g. from about 0 mg to about 15 mg        (especially 9 mg); and    -   talc, e.g. from about 0 mg to about 15 mg (especially 9 mg).

Depending from need of stabilizer the amount of L-arginine may be in therange from 0.5 mg to 10 mg. With different dose and different arginineamount, the arginine amount may be substituted by hydroxypropylmethylcellulose (HPMC).

In an embodiment, polyethylene glycol and propylene glycol are mutuallyexclusive in above composition, i.e. if polyethylene glycol is presentthen propylene glycol is absent, or if propylene glycol is present thenpolyethylene glycol is absent.

The composition of a representative linagliptin containing film coatsuspension further comprises water, e.g. from about 240 mg to about 1440mg, especially in the range from 904 mg to 1440 mg. The total solidsconcentration of the suspension is from about 4% to about 12.5% w/w,especially from 4% to 6% w/w. Viscosity may be from about 10 mPas to 110mPas (e.g. 46-56 mPas).

The sum solids of the linagliptin coating suspension is from about 50 mgto about 120 mg. For example, the sum solids is 60 mg of solid amount ofthe film coating suspension for 2.5 mg linagliptin, and 120 mg sum solidamount of the film coating suspension for 5 mg linagliptin. Thereforewith the same formulation of linagliptin and double coating time (i.e.double amount of coating suspension) it is possible to prepare thehigher dose range of linagliptin. Hence different dosage strengths canbe achieved by altering coating (spraying) times.

(b2)1-Chloro-4-(β-D-Glucopyranos-1-Yl)-2-[4-((S)-Tetrahydrofuran-3-Yloxy)-Benzyl]-BenzenePart

In another variant, the second part in the present invention is a part(composition, particularly film coat) comprising1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenein immediate release form.

In another particular embodiment, the fixed-dose combination products ofthe present invention comprise—as second part—a film coat formulation of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,said film coat formulation comprising1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,a film-coating agent (such as e.g. hydroxypropyl methylcellulose, e.g.Hypromellose 2910, Methocel E5, or Methocel E15), a plasticizer (such ase.g. polyethylene glycol, e.g. Macrogol 400, 6000 or 8000, or propyleneglycol), and, optionally, a glidant (such as e.g. talc).

The composition of a representative1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenecontaining film coat is provided as follows:

-   -   1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,        e.g. 5 mg, 10 mg, 12.5 mg or 25 mg;    -   optionally, L-arginine, e.g. from about 5 mg to about 25 mg;    -   hydroxypropyl methylcellulose (e.g. Methocel E5, Methocel E15,        or Pharmacoat 603 or 606), e.g. from about 25 mg to about 40 mg        (especially from 34.5 mg to 38 mg, or 34.5 mg);    -   polyethylene glycol (e.g. Macrogol 400, 6000 or 8000), e.g. from        about 0 to about 12 mg;    -   propylene glycol, e.g. from about 0 mg to about 15 mg        (especially 9 mg); and    -   talc, e.g. from about 0 mg to about 15 mg (especially 9 mg).

With different dose and different arginine amount, the arginine amountmay be substituted by hydroxypropyl methylcellulose (HPMC).

In an embodiment, polyethylene glycol and propylene glycol are mutuallyexclusive in above composition, i.e. if polyethylene glycol is presentthen propylene glycol is absent, or if propylene glycol is present thenpolyethylene glycol is absent.

The composition of a representative1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenecontaining film coat suspension further comprises water, e.g. from about240 mg to about 1440 mg, especially in the range from 904 mg to 1440 mg.The total solids concentration of the suspension is from about 4% toabout 12.5% w/w, especially from 4% to 6% w/w.

The sum solids of the1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenecoating suspension is from about 50 mg to about 120 mg. For example, thesum solids is 60 mg of solid amount of the film coating suspension for12.5 mg1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,and 120 mg sum solid amount of the film coating suspension for 25 mg1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.Therefore with the same formulation of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand double coating time (i.e. double amount of coating suspension) it ispossible to prepare the higher dose range of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.Hence different dosage strengths can be achieved by altering coating(spraying) times.

L-Arginine is preferably necessary for the stabilization of linagliptin.Alternatively, a seal coat may be used between the metformin XR core andthe linagliptin-containing film coat. In one embodiment, a seal coat ispresent between the metformin XR core and the linagliptin-containingfilm coat (optionally further containing L-arginine). In anotherembodiment, the seal coat is absent between the metformin XR core andthe linagliptin-containing film coat (preferably further containingL-arginine).

For Compound “A” preferably no arginine is necessary. For Compound “A”the seal coating of metformin XR cores is optional. In one embodiment, aseal coat is present between the metformin XR core and the Compound “A”containing film coat. In another embodiment, the seal coat is absentbetween the metformin XR core and the Compound “A” containing film coat.

Alternatively, for the API (linagliptin or Compound “A”) containing filmcoat, a film coat comprising a mixture of hydroxypropylcellulose andhydroxypropyl methylcellulose, or a mixture of polyvinyl alcohol (PVA)and polyethylene glycol (PEG); or a commercial film-coat such asOpadry®, Opadry II® or other Opardy IR film coat, which are formulatedpowder blends provided by Colorcon, may be used. With Opadry II or PVAbased API coating higher solid concentrations and shorter coating timedurations are possible, therefore it works in a range of 10-30%,especially 20% solid concentration. This higher solid concentration,e.g. 20%, typically results in a shorter coating time, e.g. 2-5 hours.

For example, further versions of API-containing film coat compositionscomprising one or more of the following ingredients of Tables 1 or 2 maybe provided, e.g. as follows from Tables 1 or 2:

TABLE 1 Example formulations for API-coating of linagliptin on top ofmetformin XR cores PEG- containing PG- PG- PEG- version containingcontaining Further Further containing (reduced version version versionversion version arginine) (low DL) (high DL) (e.g. (e.g. Composition (%(e.g. 2.5 mg (e.g. 5 mg (e.g. 2.5 mg (e.g. 2.5 mg 2.5 mg 5 mg w/w) API)API) API) API) API) API) Linagliptin 4.20 4.39 4.55 5.29 4.16 4.16 HPMC(e.g 67.23 70.18 72.73 70.55 — — Pharmacoat 615)* HPMC (e.g — — — — 57.557.5 Methocel E5) Polyethylene 20.17 21.05 — — 15 15 glycol (e.g. PEG6000) Propylene glycol — — 3.64 3.53 — — L-Arginine 8.40 4.39 9.09 10.588.33 8.33 Talc — — 10.00 10.05 15 15 Purified water ** ** ** ** ** **Total 100.00 100.00 100.00 100.00 100.00 100.00 Solid content of 5.955.70 5.50 5.67 4.0 4.0 suspension (%) *Alternative Methocel E15 **Solvent is a volatile component, which does not remain in the finalproduct

In one embodiment of the API coatings of this invention, thefilm-coating agent used is highly viscous.

In another embodiment of the API coatings of this invention, thefilm-coating agent used is low viscous.

TABLE 2 Further Example formulations for API-coating of linagliptin ontop of metformin XR cores: PEG- containing PG- PG- PEG- versioncontaining containing containing (reduced version version versionarginine) (low DL) (high DL) Composition (e.g. 2.5 (e.g. 5 mg (e.g. 2.5mg (e.g. 2.5 mg (% w/w) mg API) API) API) API) Linagliptin 4.20 4.394.55 5.29 HPMC (e.g. 67.23 70.18 72.73 70.55 Pharmacoat 615)Polyethylene glycol 20.17 21.05 — — (e.g. PEG 6000) Propylene glycol — —3.64 3.53 L-Arginine 8.40 4.39 9.09 10.58 Talc — — 10.00 10.05 Purifiedwater ** ** ** ** Total 100.00 100.00 100.00 100.00 Solid content of5.95 5.70 5.50 5.67 suspension (%) ** Solvent is a volatile component,which does not remain in the final product

Film coating suspensions/solutions of API (linagliptin or Compound “A”)according to this invention can be prepared by common methods, such asfollows:

The film-coating agent hydroxypropyl methylcellulose (HPMC), theplasticizer polyethylene glycol (PEG) (e.g. Macrogol 400, 6000 or 8000)or, as alternative plasticizer, propylene glycol (PG) and water aredissolved and mixed by a suitable mixer (e.g. by propeller mixer) toproduce the API-free coating solution. Optionally, the glidant talcsuspended in water is added and the obtained suspension is homogenized.Talc may be used optionally.

The API (linagliptin or Compound “A”) and—preferably in case oflinagliptin—the stabilizer L-arginine are dissolved or suspended inwater and added to the aqueous solution of HPMC, PEG or PG, and,optional talc, and dispersed by a suitable mixer (e.g. by propellermixer) to provide the API coating suspension.

Alternatively, the film-coating agent hydroxypropyl methylcellulose(HPMC) and water are dissolved and mixed by a suitable mixer (e.g. byUltraturrax).

The stabilizer L-arginine (which is present in case of linagliptin, andmay be absent in case of Compound “A”), the plasticizer polyethyleneglycol (PEG) (e.g. Macrogol 400, 6000 or 8000) or propylene glycol (PG),optional talc, and water are dispersed, e.g. by homogenization usinge.g. ultra turrax.

After degassing of the HPMC solution (or directly after manufacturing ofthe HPMC solution), the aqueous suspension of PEG or PG, optionalL-arginine and optional talc are added to the aqueous HPMC solution andmixed/homogenized.

The API (linagliptin or Compound “A”) is dissolved or suspended in waterand added to the aqueous solution of HPMC, PEG or PG, optionalL-arginine and optional talc to provide the API coating suspension.

The film-coating operation is carried out in a conventional film coater.The API (linagliptin or Compound “A”) coating suspension/solution arecoated at metformin XR cores via coating process.

Preliminary preheating of the cores may be necessary, due to need ofequilibrium of water amount of the cores.

The spray rate and air flow through the coating pan is adjusted toproduce a uniform coating and coverage of the entire width of the tabletbed. The amount of the coating suspension applied can be controlled bypercent weight gain of tablet cores and typically ranges from about 4 toabout 12.5%.

In one aspect, this range results in linagliptin drug assay close to thedesired 2.5 mg or 5 mg with a standard deviation of about 2-4% forcontent uniformity assay of linagliptin. The duration of the coatingstep is about 4-10 hours. The duration of the coating step depends onbatch size, process parameters like spray rate and solid concentrationsof the coating suspension.

In another aspect, this range results in Compound “A” drug assay closeto the desired 5 mg, 12.5 mg, 10 mg or 25 mg with a standard deviationof about 2-4% for content uniformity assay of Compound “A”. The durationof the coating step is about 4-10 hours. The duration of the coatingstep depends on batch size, process parameters like spray rate and solidconcentrations of the coating suspension.

The API coating suspension is applied to the tablet cores containing themetformin XR formulation and the amount of solids deposited in the APIfilm layer is controlled to achieve the desired API doses.

The weight of the cores and film coated tablets may be controlled bypercent weight gain during the coating process. Instead of or inaddition to weight gain method a PAT method, e.g. online NIR or Ramanmethod for end point detection of assay of API may be used.

An optional seal coat may separate the metformin XR core from theAPI-containing film coat. Typically, for the preparation of film-coatedtablets a coating suspension is prepared and the tablet cores may becoated with the seal coating suspension using standard film coater.

The film coating solvent is a volatile component, which does not remainin the final product. A typical seal film-coat comprises a film coatingagent, a plasticizer, and, optionally, a glidant, one or more pigmentsand/or colors.

The metformin XR core may be seal coated using a seal coating agent (anda plasticizer), such as with a mixture of hydroxypropylcellulose andhydroxypropyl methylcellulose, a mixture of polyvinyl alcohol (PVA) andpolyethylene glycol (PEG), a mixture of hydroxypropyl methylcelluloseand either polyethylene glycol (PEG) or propylene glycol (PG), or anyother suitable immediate-release film-coating agent(s). A commercialfilm-coat is Opadry®, Opadry II® or other Opardy IR film coat, which areformulated powder blend provided by Colorcon. Optionally the seal coatmay further comprise a glidant.

The final pharmaceutical compositions of the present invention aretablets. Such tablets may be further film-coated with a final filmover-coat, such as with a mixture of hydroxypropylcellulose andhydroxypropyl methylcellulose containing titanium dioxide and/or othercoloring agents, such as iron oxides, dyes, and lakes; a mixture ofpolyvinyl alcohol (PVA) and polyethylene glycol (PEG) containingtitanium dioxide and/or other coloring agents, such as iron oxides,dyes, and lakes; a mixture of hydroxypropyl methylcellulose and eitherpolyethylene glycol (PEG) or propylene glycol (PG) containing titaniumdioxide and/or other coloring agents, such as iron oxides, dyes, andlakes; or any other suitable immediate-release film-coating agent(s).The coat may provide taste masking and additional stability to the finaltablet. A commercial film-coat is Opadry®, Opadry II® or other Opardy IRfilm coat, which are formulated powder blend provided by Colorcon.

Preferably, for the preparation of film-coated tablets a coatingsuspension is prepared and the tablet cores are coated with the coatingsuspension, typically for the API-free film over-coat to a weight gainof about 2-4%, preferably about 3%, using standard film coater.

The film coating solvent is a volatile component, which does not remainin the final product. A typical film-coat comprise a film coating agent,a plasticizer, and, optionally, a glidant, one or more pigments and/orcolors. For example, the film coat may comprisehydroxypropylmethylcellulose (HPMC), propylene glycol or polyethyleneglycol, talc and, optionally, titanium dioxide and/or iron oxide (e.g.iron oxide yellow and/or red).

The pharmaceutical tablet compositions of the present invention may alsocontain one or more additional formulation ingredients selected from awide variety of excipients known in the pharmaceutical formulation art.According to the desired properties of the pharmaceutical composition,any number of ingredients may be selected, alone or in combination,based upon their known uses in preparing tablet compositions. Suchingredients include, but are not limited to, diluents, compression aids,glidants, disintegrants, lubricants, flavors, flavor enhancers,sweeteners, and preservatives.

The term “tablet” as used herein is intended to encompass compressedpharmaceutical dosage formulations of all shapes and sizes.

The present invention also provides methods particularly for treatingType 2 diabetes by orally administering to a host in need of suchtreatment a therapeutically effective amount of one of the fixed-dosecombination pharmaceutical compositions of the present invention. In oneembodiment the host in need of such treatment is a human. In anotherembodiment the pharmaceutical composition is in the dosage form of atablet. The pharmaceutical compositions comprising the fixed-dosecombination may be administered once-daily (QD), twice-daily (BID),thrice-daily (TID), or four-times daily.

Manufacture and Polymorph

The term “linagliptin” as employed herein refers to linagliptin, apharmaceutically acceptable salt thereof, a hydrate or solvate thereof,or a polymorphic form thereof. Crystalline forms are described in WO2007/128721. Preferred crystalline forms are the polymorphs A and Bdescribed therein. In particular, linagliptin is the free base1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.As linagliptin or a pharmaceutically acceptable salt thereof,linagliptin is preferred. Methods for the manufacture of linagliptin aredescribed in the patent applications WO 2004/018468 and WO 2006/048427for example.

1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(linagliptin)

According to this invention, it is to be understood that the definitionof the SGLT2 inhibitor, in particular1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene(Compound “A”), also comprises its hydrates, solvates and polymorphicforms thereof, and prodrugs thereof. With regard to the preferred1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzenean advantageous crystalline form is described in the internationalpatent application WO 2006/117359 which hereby is incorporated herein inits entirety. This crystalline form possesses good solubility propertieswhich enable a good bioavailability of the SGLT2 inhibitor. Furthermore,the crystalline form is physico-chemically stable and thus provides agood shelf-life stability of the pharmaceutical composition.

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene(Compound “A”)

Methods for the manufacture of SGLT2 inhibitors according to thisinvention and of prodrugs thereof are known to the one skilled in theart. Advantageously, the compounds according to this invention can beprepared using synthetic methods as described in the literature,including patent applications as cited hereinbefore. Preferred methodsof manufacture, in particular of1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,are described in the WO 2006/120208.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above in connection with the specified SGLT2 or DPP-4inhibitors is specifically incorporated herein by reference in itsentirety.

Indications

As described herein by the administration of the pharmaceuticalcomposition according to this invention, therapeutic effects can beachieved, which make it useful for treating and/or preventing certaindiseases, disorders or conditions, such as e.g. those described herein.

Therefore, a treatment or prophylaxis according to this invention isadvantageously suitable in those patients in need of such treatment orprophylaxis who are diagnosed of one or more of the conditions selectedfrom the group consisting of overweight and obesity, in particular classI obesity, class II obesity, class III obesity, visceral obesity andabdominal obesity. In addition a treatment or prophylaxis according tothis invention is advantageously suitable in those patients in which aweight increase is contraindicated. The pharmaceutical composition aswell as the methods according to the present invention allow a reductionof the HbA1c value to a desired target range, for example <7% andpreferably <6.5%, for a higher number of patients and for a longer timeof therapeutic treatment compared with a corresponding monotherapy.

The pharmaceutical composition according to this invention and inparticular the active ingredients therein exhibits a very good efficacywith regard to glycemic control, in particular in view of a reduction offasting plasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin (HbA1c). By administering a pharmaceutical compositionaccording to this invention, a reduction of HbA1c equal to or greaterthan preferably 0.5%, even more preferably equal to or greater than 1.0%can be achieved and the reduction is particularly in the range from 1.0%to 2.0%.

Furthermore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   (a) a fasting blood glucose or serum glucose concentration greater    than 110 mg/dL, in particular greater than 125 mg/dL;-   (b) a postprandial plasma glucose equal to or greater than 140    mg/dL;-   (c) an HbA1c value equal to or greater than 6.5%, in particular    equal to or greater than 7.0%, especially equal to or greater than    7.5%, even more particularly equal to or greater than 8.0%.

The present invention also discloses the use of the pharmaceuticalcomposition for improving glycemic control in patients having type 2diabetes or showing first signs of pre-diabetes. Thus, the inventionalso includes diabetes prevention. If therefore a pharmaceuticalcomposition according to this invention is used to improve the glycemiccontrol as soon as one of the above-mentioned signs of pre-diabetes ispresent, the onset of manifest type 2 diabetes mellitus can be delayedor prevented.

Furthermore, the pharmaceutical composition according to this inventionis particularly suitable in the treatment of patients with insulindependency, i.e. in patients who are treated or otherwise would betreated or need treatment with an insulin or a derivative of insulin ora substitute of insulin or a formulation comprising an insulin or aderivative or substitute thereof. These patients include patients withdiabetes type 2 and patients with diabetes type 1.

Therefore, according to a preferred embodiment of the present invention,there is provided a method for improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patient in need thereof whois diagnosed with impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG) with insulin resistance, with metabolic syndromeand/or with type 2 or type 1 diabetes mellitus characterized in that apharmaceutical composition as defined hereinbefore and hereinafter isadministered to the patient.

According to another preferred embodiment of the present invention,there is provided a method for improving glycemic control in patients,in particular in adult patients, with type 2 diabetes mellitus as anadjunct to diet and exercise.

Therefore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   (a) insufficient glycemic control with diet and exercise alone;-   (b) insufficient glycemic control despite oral monotherapy with    metformin, in particular despite oral monotherapy at a maximal    tolerated dose of metformin;-   (c) insufficient glycemic control despite oral monotherapy with    another antidiabetic agent, in particular despite oral monotherapy    at a maximal tolerated dose of the other antidiabetic agent.

The lowering of the blood glucose level by the administration of apharmaceutical composition according to this invention isinsulin-independent. Therefore, a pharmaceutical composition accordingto this invention is particularly suitable in the treatment of patientswho are diagnosed having one or more of the following conditions

-   -   insulin resistance,    -   hyperinsulinemia,    -   pre-diabetes,    -   type 2 diabetes mellitus, particular having a late stage type 2        diabetes mellitus,    -   type 1 diabetes mellitus.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   (a) obesity (including class I, II and/or III obesity), visceral    obesity and/or abdominal obesity,-   (b) triglyceride blood level≧150 mg/dL,-   (c) HDL-cholesterol blood level<40 mg/dL in female patients and <50    mg/dL in male patients,-   (d) a systolic blood pressure≧130 mm Hg and a diastolic blood    pressure≧85 mm Hg,-   (e) a fasting blood glucose level≧110 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance(IGT), impaired fasting blood glucose (IFG), with insulin resistanceand/or with metabolic syndrome suffer from an increased risk ofdeveloping a cardiovascular disease, such as for example myocardialinfarction, coronary heart disease, heart insufficiency, thromboembolicevents. A glycemic control according to this invention may result in areduction of the cardiovascular risks.

A pharmaceutical composition according to this invention exhibits a goodsafety profile. Therefore, a treatment or prophylaxis according to thisinvention is advantageously possible in those patients for which themono-therapy with another antidiabetic drug is contraindicated and/orwho have an intolerance against such drugs at therapeutic doses. Inparticular, a treatment or prophylaxis according to this invention maybe advantageously possible in those patients showing or having anincreased risk for one or more of the following disorders: renalinsufficiency or diseases, cardiac diseases, cardiac failure, hepaticdiseases, pulmonal diseases, catabolytic states and/or danger of lactateacidosis, or female patients being pregnant or during lactation.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

A pharmaceutical composition according to this invention is particularlysuitable in the long term treatment or prophylaxis of the diseasesand/or conditions as described hereinbefore and hereinafter, inparticular in the long term glycemic control in patients with type 2diabetes mellitus.

The term “long term” as used hereinbefore and hereinafter indicates atreatment of or administration in a patient within a period of timelonger than 12 weeks, preferably longer than 25 weeks, even morepreferably longer than 1 year.

Therefore, a particularly preferred embodiment of the present inventionprovides a method for therapy, preferably oral therapy, for improvement,especially long term improvement, of glycemic control in patients withtype 2 diabetes mellitus, especially in patients with late stage type 2diabetes mellitus, in particular in patients additionally diagnosed ofoverweight, obesity (including class I, class II and/or class IIIobesity), visceral obesity and/or abdominal obesity.

According to another aspect of the invention, there is provided a methodfor preventing, slowing the progression of, delaying or treating of acondition or disorder selected from the group consisting ofcomplications of diabetes mellitus such as cataracts and micro- andmacrovascular diseases, such as dyslipidemia, nephropathy, retinopathy,neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis,myocardial infarction, acute coronary syndrome, unstable anginapectoris, stable angina pectoris, stroke, peripheral arterial occlusivedisease, cardiomyopathy, heart failure, heart rhythm disorders andvascular restenosis, in a patient in need thereof characterized in thata pharmaceutical composition according to the invention is administeredto the patient. In particular one or more aspects of diabeticnephropathy such as hyperperfusion, proteinuria and albuminuria may betreated, their progression slowed or their onset delayed or prevented.The term “tissue ischaemia” particularly comprises diabeticmacroangiopathy, diabetic microangiopathy, impaired wound healing anddiabetic ulcer. The terms “micro- and macrovascular diseases” and“micro- and macrovascular complications” are used interchangeably inthis application.

According to another aspect of the invention, there is provided a methodfor preventing, slowing the progression of, delaying or treating ametabolic disorder selected from the group consisting of type 2 diabetesmellitus, impaired glucose tolerance (IGT), impaired fasting bloodglucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight,obesity, metabolic syndrome, gestational diabetes and diabetes relatedto cystic fibrosis in a patient in need thereof characterized in that apharmaceutical composition according to the invention is administered tothe patient.

According to another aspect of the invention, there is provided a methodfor improving glycemic control and/or for reducing of fasting plasmaglucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c in a patient in need thereof characterized in that a apharmaceutical composition according to the invention is administered tothe patient.

The pharmaceutical composition according to this invention may also havevaluable disease-modifying properties with respect to diseases orconditions related to impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG), insulin resistance and/or metabolic syndrome.

According to another aspect of the invention, there is provided a methodfor preventing, slowing, delaying or reversing progression from impairedglucose tolerance (IGT), impaired fasting blood glucose (IFG), insulinresistance and/or from metabolic syndrome to type 2 diabetes mellitus ina patient in need thereof characterized in that a pharmaceuticalcomposition according to the invention is administered to the patient.

As by the use of a pharmaceutical composition according to thisinvention, an improvement of the glycemic control in patients in needthereof is obtainable, also those conditions and/or diseases related toor caused by an increased blood glucose level may be treated.

By the administration of a pharmaceutical composition according to thisinvention excessive blood glucose levels are not converted to insolublestorage forms, like fat, but excreted through the urine of the patient.It can be seen that loss of fat may account for the majority of theobserved weight loss whereas no significant changes in body water orprotein content are observed. Therefore, no gain in weight or even areduction in body weight is the result.

According to another aspect of the invention, there is provided a methodfor reducing body weight and/or body fat or preventing an increase inbody weight and/or body fat or facilitating a reduction in body weightand/or body fat in a patient in need thereof characterized in that apharmaceutical composition according to the invention is administered tothe patient.

By the administration of a combination or pharmaceutical compositionaccording to the present invention, an abnormal accumulation of ectopicfat, in particular of the liver, may be reduced or inhibited. Therefore,according to another aspect of the present invention, there is provideda method for preventing, slowing, delaying or treating diseases orconditions attributed to an abnormal accumulation of ectopic fat, inparticular of the liver, in a patient in need thereof characterized inthat a pharmaceutical composition according to the invention isadministered to the patient. Diseases or conditions which are attributedto an abnormal accumulation of liver fat are particularly selected fromthe group consisting of general fatty liver, non-alcoholic fatty liver(NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-inducedfatty liver, diabetic fatty liver, alcoholic-induced fatty liver ortoxic fatty liver.

Another aspect of the invention provides a method for maintaining and/orimproving the insulin sensitivity and/or for treating or preventinghyperinsulinemia and/or insulin resistance in a patient in need thereofcharacterized in that a pharmaceutical composition according to theinvention is administered to the patient.

According to another aspect of the invention, there is provided a methodfor preventing, slowing progression of, delaying, or treating new onsetdiabetes after transplantation (NODAT) and/or post-transplant metabolicsyndrome (PTMS) in a patient in need thereof characterized in that apharmaceutical composition according to the invention is administered tothe patient.

According to a further aspect of the invention, there is provided amethod for preventing, delaying, or reducing NODAT and/or PTMSassociated complications including micro- and macrovascular diseases andevents, graft rejection, infection, and death in a patient in needthereof characterized in that a pharmaceutical composition according tothe invention is administered to the patient.

The pharmaceutical composition according to the invention is capable offacilitating the lowering of serum total urate levels in the patient.Therefore according to another aspect of the invention, there isprovided a method for treating hyperuricemia andhyperuricemia-associated conditions, such as for example gout,hypertension and renal failure, in a patient in need thereofcharacterized in that a pharmaceutical composition according to theinvention is administered to the patient.

The administration of a pharmaceutical composition increases the urineexcretion of glucose. This increase in osmotic excretion and waterrelease and the lowering of urate levels are beneficial as a treatmentor prevention for kidney stones. Therefore in a further aspect of theinvention, there is provided a method for treating or preventing kidneystones in a patient in need thereof characterized in that apharmaceutical composition according to the invention is administered tothe patient.

The invention also relates to a pharmaceutical composition according tothis invention for use in a method as described hereinbefore andhereinafter.

The invention also relates to a use of a pharmaceutical compositionaccording to this invention for the manufacture of a medicament for usein a method as described hereinbefore and hereinafter.

DEFINITIONS

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor, the DPP-4 inhibitorand/or metformin according to the present invention.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The term “obesity” is defined as the condition wherein the individualhas a BMI equal to or greater than 30 kg/m². According to a WHOdefinition the term obesity may be categorized as follows: the term“class I obesity” is the condition wherein the BMI is equal to orgreater than 30 kg/m² but lower than 35 kg/m²; the term “class IIobesity” is the condition wherein the BMI is equal to or greater than 35kg/m² but lower than 40 kg/m²; the term “class III obesity” is thecondition wherein the BMI is equal to or greater than 40 kg/m².

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference≧85 cm in men and ≧90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range, in particularbelow 70 mg/dL (3.89 mmol/L) or even below 60 mg/dl.

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.1 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.8 mmol/L) and lessthan 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e. the2 hour postprandial blood glucose or serum glucose concentration can bemeasured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.8 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio<1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl. 1): A459) and to an euglycemic clamp study. In addition,plasma adiponectin levels can be monitored as a potential surrogate ofinsulin sensitivity. The estimate of insulin resistance by thehomeostasis assessment model (HOMA)-IR score is calculated with theformula (Galvin P, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese, but this is not always the case. Ifinsulin resistance can be detected, this is a particularly strongindication of the presence of pre-diabetes. Thus, it may be that inorder to maintain glucose homeostasis a person have e.g. 2-3 times ashigh endogenous insulin production as a healthy person, without thisresulting in any clinical symptoms.

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index forbeta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl. 1): A459), the insulin/C-peptide secretion after an oralglucose tolerance test or a meal tolerance test, or by employing ahyperglycemic clamp study and/or minimal modeling after a frequentlysampled intravenous glucose tolerance test (Stumvoll et al., Eur J ClinInvest 2001, 31: 380-81).

The term “pre-diabetes” is the condition wherein an individual ispre-disposed to the development of type 2 diabetes. Pre-diabetes extendsthe definition of impaired glucose tolerance to include individuals witha fasting blood glucose within the high normal range 100 mg/dL (J. B.Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia(elevated plasma insulin concentration). The scientific and medicalbasis for identifying pre-diabetes as a serious health threat is laidout in a Position Statement entitled “The Prevention or Delay of Type 2Diabetes” issued jointly by the American Diabetes Association and theNational Institute of Diabetes and Digestive and Kidney Diseases(Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can beconfirmed in these individuals by calculating the HOMA-IR score. For thepurpose of this invention, insulin resistance is defined as the clinicalcondition in which an individual has a HOMA-IR score>4.0 or a HOMA-IRscore above the upper limit of normal as defined for the laboratoryperforming the glucose and insulin assays.

The term “type 1 diabetes” is defined as the condition in which asubject has, in the presence of autoimmunity towards the pancreaticbeta-cell or insulin, a fasting blood glucose or serum glucoseconcentration greater than 125 mg/dL (6.94 mmol/L). If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach, in thepresence of autoimmunity towards the pancreatic beta cell or insulin. Ina glucose tolerance test 75 g of glucose are administered orally to thepatient being tested after 10-12 hours of fasting and the blood sugarlevel is recorded immediately before taking the glucose and 1 and 2hours after taking it. The presence of autoimmunity towards thepancreatic beta-cell may be observed by detection of circulating isletcell autoantibodies [“type 1A diabetes mellitus”], i.e., at least oneof: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm],IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like proteinIA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs ofautoimmunity without the presence of typical circulating autoantibodies[type 1B diabetes], i.e. as detected through pancreatic biopsy orimaging). Typically a genetic predisposition is present (e.g. HLA, INSVNTR and PTPN22), but this is not always the case.

The term “type 2 diabetes” is defined as the condition in which asubject has a fasting blood glucose or serum glucose concentrationgreater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucosevalues is a standard procedure in routine medical analysis. If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach. In a glucosetolerance test 75 g of glucose are administered orally to the patientbeing tested after 10-12 hours of fasting and the blood sugar level isrecorded immediately before taking the glucose and 1 and 2 hours aftertaking it. In a healthy subject, the blood sugar level before taking theglucose will be between 60 and 110 mg per dL of plasma, less than 200 mgper dL 1 hour after taking the glucose and less than 140 mg per dL after2 hours. If after 2 hours the value is between 140 and 200 mg, this isregarded as abnormal glucose tolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference>40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference≧85 cm in men and ≧90 cm in women;    -   2. Triglycerides: ≧150 mg/dL    -   3. HDL-cholesterol<40 mg/dL in men    -   4. Blood pressure≧130/85 mm Hg (SBP≧130 or DBP≧85)    -   5. Fasting blood glucose≧100 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor and Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis suffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The definitions of NODAT (new onset diabetes after transplantation) andPTMS (post-transplant metabolic syndrome) follow closely that of theAmerican Diabetes Association diagnostic criteria for type 2 diabetes,and that of the International Diabetes Federation (IDF) and the AmericanHeart Association/National Heart, Lung, and Blood Institute, for themetabolic syndrome. NODAT and/or PTMS are associated with an increasedrisk of micro- and macrovascular disease and events, graft rejection,infection, and death. A number of predictors have been identified aspotential risk factors related to NODAT and/or PTMS including a higherage at transplant, male gender, the pre-transplant body mass index,pre-transplant diabetes, and immunosuppression.

The term “gestational diabetes” (diabetes of pregnancy) denotes a formof the diabetes which develops during pregnancy and usually ceases againimmediately after the birth. Gestational diabetes is diagnosed by ascreening test which is carried out between the 24th and 28th weeks ofpregnancy. It is usually a simple test in which the blood sugar level ismeasured one hour after the administration of 50 g of glucose solution.If this 1 h level is above 140 mg/dl, gestational diabetes is suspected.Final confirmation may be obtained by a standard glucose tolerance test,for example with 75 g of glucose.

The term “hyperuricemia” denotes a condition of high serum total uratelevels. In human blood, uric acid concentrations between 3.6 mg/dL (ca.214 μmol/L) and 8.3 mg/dL (ca. 494 μmol/L) are considered normal by theAmerican Medical Association. High serum total urate levels, orhyperuricemia, are often associated with several maladies. For example,high serum total urate levels can lead to a type of arthritis in thejoints known as gout. Gout is a condition created by a build up ofmonosodium urate or uric acid crystals on the articular cartilage ofjoints, tendons and surrounding tissues due to elevated concentrationsof total urate levels in the blood stream. The build up of urate or uricacid on these tissues provokes an inflammatory reaction of thesetissues. Saturation levels of uric acid in urine may result in kidneystone formation when the uric acid or urate crystallizes in the kidney.Additionally, high serum total urate levels are often associated withthe so-called metabolic syndrome, including cardiovascular disease andhypertension.

The term “hyponatremia” denotes a condition of a positive balance ofwater with or without a deficit of sodium, which is recognized when theplasma sodium falls below the level of 135 mml/L. Hyponatremia is acondition which can occur in isolation in individuals that over-consumewater; however, more often hyponatremia is a complication of medicationor other underlying medical condition that leas to a diminishedexcretion of water. Hyponatremia may lead to water intoxication, whichoccurs when the normal tonicity of extracellular fluid falls below thesafe limit, due to retention of excess water. Water intoxication is apotentially fatal disturbance in brain function. Typical symptoms ofwater intoxication include nausea, vomiting, headache and malaise.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventively treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

1. A pharmaceutical composition comprising: a) an inner extended releasecore comprising metformin or metformin hydrochloride and one or moreexcipients; b) an optional intermediate seal coating; and c) an outerimmediate release coating comprising at least one active pharmaceuticalingredient, wherein said at least one pharmaceutical ingredient is aSGLT-2 inhibitor, and one or more excipients.
 2. The pharmaceuticalcomposition according to claim 1, wherein the inner extended releasecore a) is a formulation comprising metformin hydrochloride, a swellableand/or extended release polymer, and one or more further excipients. 3.(canceled)
 4. (canceled)
 5. The pharmaceutical composition according toclaim 1, wherein the outer immediate release coating c) is a film coatformulation comprising1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,a film-coating agent, a plasticizer, and, optionally, a glidant. 6.(canceled)
 7. The pharmaceutical composition according to claim 5,wherein the film-coating agent is hydroxypropyl methylcellulose, e.g.Hypromellose 2910, Methocel E5, or Methocel E15.
 8. (canceled)
 9. Thepharmaceutical composition according to claim 5, wherein the plastiziceris polyethylene glycol, e.g. Macrogol 400, 6000 or
 8000. 10. (canceled)11. The pharmaceutical composition according to claim 5, wherein theplastizicer is propylene glycol
 12. (canceled)
 13. The pharmaceuticalcomposition according to claim 5, wherein the optional glidant is talc.14. The pharmaceutical composition according to claim 1, wherein theseal coating is present.
 15. The pharmaceutical composition according toclaim 14, wherein the seal coating comprises a film-coating agent, aplasticizer, and, optionally, a glidant, one or more pigments and/orcolors.
 16. The pharmaceutical composition according to claim 1, whereinthe seal coating is absent.
 17. The pharmaceutical composition accordingto claim 1, wherein the metformin hydrochloride is present in a unitdosage strength of 500, 750, 850, 1000 or 1500 mg.
 18. (canceled) 19.The pharmaceutical composition according to claim 1, wherein the SGLT-2inhibitor is1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneand is present in a unit dosage strength of 5, 10, 12.5 or 25 mg. 20.The pharmaceutical composition according to claim 1, which is a tabletfor oral administration.
 21. The tablet according to claim 20 furthercomprising an outer film over-coat.
 22. The tablet according to claim21, wherein the outer film over-coat comprises a film-coating agent, aplasticizer, and, optionally, a glidant, one or more pigments and/orcolors.
 23. A method of using the pharmaceutical composition accordingto claim 1 for treating, preventing, slowing the progression, ordelaying the onset of metabolic diseases either in type 2 diabetespatients who have not been previously treated with an antihyperglycemicagent, or in type 2 diabetes patients with insufficient glycemic controldespite therapy with one or two conventional antihyperglycemic agentsselected from metformin, sulphonylureas, thiazolidinediones, glinides,alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin orinsulin analogues.
 24. The method of claim 23, wherein the metabolicdisease is type 2 diabetes mellitus and conditions related thereto. 25.The method of claim 23, wherein the SGLT-2 inhibitor is1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.26. A pharmaceutical composition comprising: a) an inner extendedrelease core comprising metformin hydrochloride and one or moreexcipients; b) an optional intermediate seal coating; and c) an outerimmediate release coating comprising at least one active pharmaceuticalingredient, wherein said at least one active pharmaceutical ingredientis1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,and one or more excipients.
 27. The pharmaceutical composition accordingto claim 26 which is a tablet for oral administration.